The selective conversion of one functional group in a multifunctional feed substrate has been an area of continuous high interest throughout the chemical, pharmaceutical and agrochemical industry. In particular, halogen atoms are often incorporated next to other functional groups in active ingredients or in precursors of those active ingredients.
The objective of high selectivity has often been rather elusive, because most processes are prone to side reactions leading to significant amounts of byproducts. These side reactions are consuming valuable amounts of feed substrate, and the byproducts are often rather useless. Some of the byproducts may also be difficult to separate from the desired product. In cases where the desired product is an intermediate for the production of a further derivative, some of the byproducts may also be disturbing for further synthesis steps because they may be reactive in such downstream process step and may lead to undesired additional consumption of valuable raw materials and even to undesirable and/or unacceptable end product contamination.
Multi-step synthesis protocols of complex multifunctional chemicals more and more comprise catalytic conversion steps as these often outperform their stoichiometric alternatives with respect to atom efficiency and reduced waste generation. Reductive conversion steps with hydrogen gas as the reducing agent typically use metal based catalysts in order to proceed at rates of commercial interests.
Metals, however, often interfere with carbon-halogen bonds in organic compounds. Pd in particular is for instance capable of inserting into a carbon-halogen bond. Such behaviour is desired in its use as catalyst in so-called coupling reactions. Such reactions are often used as key steps in multi-step synthesis paths for complex organic compounds, such as active ingredients in pharmaceutical or agrochemical industry. In a coupling reaction, a halogen containing first fragment is coupled with a second fragment by means of a catalyst, in which the second fragment is coupled to the first fragment at the position where the halogen was originally located. The second fragment may be coupled via a large variety of functional groups, and different versions of such coupling reactions have often received specific names, such as the Heck coupling, which is using an olefin, the Sonogashira coupling, which is using an alkyne, the Suzuki coupling, which is using a boronic acid and the Stille coupling, which uses an alkyl tin group. This list is far from exhaustive, because many more different functional groups may possibly be used for such coupling.
Insertion of a metal such as Pd into a carbon-halogen bond in the presence of hydrogen but in the absence of a suitable fragment to couple usually results in the displacement of the halogen atom by a hydrogen atom and hence the loss of the halogen (X) as part of the substrate. Such hydrogenolysis reaction is especially enhanced in the presence of a base which may capture the liberated acid HX. This reaction may be used advantageously in some applications, such as environmental treatment of halogenated organic pollutants.
For the production of the halogenated fragments to be used in subsequent coupling reactions, or in case halogen atoms are required in the structure of the final product, the insertion of the metal catalyst into the carbon-halogen bond is not desired, as it usually leads to side reactions and associated material losses. Not all halogens are evenly sensitive for this dehalogenation side reaction. The risk for dehalogenation is particularly high with chlorine, bromine and iodine, and much lower with fluorine-containing substrates.
A variety of methods have therefore been attempted in order to increase the selectivity of metal catalysed reductive aminations of one functional group in the presence of one or more halogen atoms elsewhere in the substrate molecule, in particular for chlorine, bromine and iodine.
One method involves the addition of modifiers to the reaction mixture or working into alternative reaction media.
U.S. Pat. No. 5,011,996 for instance discloses in Example 14 a process for the reductive amination of ortho-chloro benzaldehyde with ammonia, in methanol, under 90 bar of nitrogen supplemented by hydrogen addition until completion of the hydrogen uptake. Methanol-moist Raney nickel was used as the catalyst and a small amount of bis-(2-hydroxyethyl) sulphide was added as a modifier. The reaction mixture contained 90.5% ortho-chloro-benzylamine as the prime product, together with 0.9% of benzylamine and 6.8% of ortho-chloro-benzyl alcohol.
U.S. Pat. No. 6,429,335 B1 discloses in Example 1 also a process for the reductive amination of ortho-chloro benzaldehyde with ammonia, now under 140 bar of hydrogen using Raney nickel or Raney cobalt, to produce the primary amine ortho-chlorobenzylamine. This process operates in the presence of an amount of disodium tetraborate decahydrate (borax), optionally together with a small amount of bis(hydroxyethyl) sulphide, and obtains a product selectivity of at most 95.87% wt. The main byproduct is 3.19% wt of ortho-chloro-benzyl alcohol, and only 0.1% wt of benzylamine was found.
WO 2014/135508 A1 and EP 2774911 A1 disclose a process for the production of ortho-chloro-N,N-dimethylbenzylamine by the reaction of ortho-chloro-benzaldehyde (2-CI-BZA) with dimethylamine (DMA), in the presence of acetic acid, hydrogen and a nickel catalyst. The examples use a molar ratio of DMA/2-CI-BZA of at least 1.5/1, and demonstrate that a higher yield of the desired product is achieved when this molar ratio is increased further.
US 2007/0078282 A1 discloses reductive amination using bifunctional catalysts containing a hydrogen-active component with an acidic oxide as cocatalyst. Only example 4 starts from a halogen-containing substrate, the halogen being fluorine. Fluorine is however known to be particularly insensitive to dehalogenation, much less than the other common halogens.
Other chemical pathways to obtain particularly valuable polyfunctional products containing halogens have also been explored.
The stoichiometric alternative to the catalytic reductive amination of o-chloro benzaldehyde to obtain o-chloro-benzyl-dimethylamine is exemplified by WO 2013/017611 A1, which describes a process to obtain o-chloro-benzyl-dimethylamine from o-chloro-benzyl chloride and dimethylamine. The yield of the reaction was at most 95.4% of theory. The reaction was performed without involving any catalyst and a chloride salt was obtained as an undesired byproduct. Such processes based on stoichiometric chemistry in general suffer from poor atom efficiency and production of large amounts of waste.
There therefore remains a need for a highly selective conversion in the reductive amination of only the first functional group, on a substrate containing at least one further functional group containing a halogen atom. The desire is to achieve industrially acceptable reaction rates while keeping the further functional group containing the halogen atom substantially untouched and present in the reaction product.
It is an objective of the process according to the present invention to carry out the selected chemical reaction with a low degree of dehalogenation. Fluorine is known to be significantly less sensitive to dehalogenation than the heavier and more bulky halogens chlorine, bromine and/or iodine. A fluorine atom initially present in the feed substrate molecule therefore has a higher likelihood to remain present in the reaction product as compared to the other halogens. There therefore remains a particular need for a highly selective catalyst which will allow a low degree of dehalogenation in a substrate containing at least one further functional group containing chlorine, bromine and/or iodine.
The present invention aims to obviate or at least mitigate the above described problem and/or to provide improvements generally.